Biomedical subjects

B B Hasinoff

Publications and source records attributed to B B Hasinoff.

At least 55 records · Page 3Linked to original sources

PubMed1994

Ferrous sulphate does not directly affect pteroylmonoglutamic acid absorption in rats.

A variety of compounds which bind to Fe have substantial reductions in absorption when co-administered with Fe compounds. The binding of both Fe2+ and Fe3+ ions to pteroylmonoglutamic acid and the pteroylmonoglutamate dianion was examined in vitro. In dimethylsulphoxide (DMSO) alone, pteroylmonoglutamate formed a 2:1 (pteroylmonoglutamate:Fe3+ ion) complex. However, in DMSO-aqueous Bis-Tris buffer (4:1, v/v; pH 6.0) no evidence of complex formation could be seen. Likewise spectroscopic evidence was obtained for complex formation with Fe2+ ion and pteroylmonoglutamate in DMSO alone but not in the aqueous DMSO buffer. In vivo studies examined the effect of FeSO4 on pteroylmonoglutamic acid absorption in an isolated perfused rat jejunal model of nutrient absorption. The dose of pteroylmonoglutamic acid approximated a human dose of 1 mg for the rat, while the FeSO4 doses were chosen to represent 6.4 mg, 64 mg and 300 mg human doses. There was no significant effect of FeSO4 on pteroylmonoglutamic acid absorption or instability of pteroylmonoglutamic acid in vivo in the presence of FeSO4 in the rat. Although 2:1 binding of pteroylmonoglutamic acid to Fe ions could be demonstrated in DMSO alone, no binding could be demonstrated in DMSO-Bis-Tris buffer (4:1, v/v; pH 6.0). It is unlikely that there will be a significant reduction in pteroylmonoglutamic acid absorption during concurrent ingestion of Fe preparations.

Animals↗

PubMed1994

Metabolism of the cardioprotective agents dexrazoxane (ICRF-187) and levrazoxane (ICRF-186) by the isolated hepatocyte.

1. The metabolism of dexrazoxane (ICRF-187) and its optical isomer levrazoxane (ICRF-186) by the isolated rat hepatocyte was studied by hplc. 2. 4-Chlorobenzenesulphonamide, which is a strong inhibitor of dihydropyrimidine amidohydrolase (DHPase), caused 82% inhibition of the loss of dexrazoxane from the hepatocyte suspension. 3. Dexrazoxane was metabolized at an initial rate by isolated hepatocytes that was 1.8 times faster than levrazoxane. This ratio is close to that found for purified DHPase, suggesting that DHPase present in the hepatocyte catalyses the ring-opening hydrolysis of these drugs. 4. The ratios of the rates at which each of the one-ring open intermediates of dexrazoxane and levrazoxane were produced in the hepatocyte suspension are also consistent with DHPase being primarily responsible for the metabolism of dexrazoxane and levrazoxane. 5. Thus, the DHPase-catalysed formation of the one-ring opened intermediates enhances the rate at which the presumably active metal-ion binding forms of dexrazoxane are produced in the hepatocyte. 6. The DHPase content of the hepatocyte was estimated to be 1.2 nmol/kg of total hepatocyte mass, or equivalently 5700 molecules of DHPase per hepatocyte.

Amidohydrolases↗

PubMed1993

Ferrous sulfate reduces cimetidine absorption.

A variety of drugs that bind to iron have significant reductions in absorption when coadministered with iron compounds. Cimetidine has a structure that would suggest strong binding to iron ions. In vitro experiments were performed to examine a variety of characteristics of the binding of iron to cimetidine. Further studies were conducted to determine the effect of concurrent administration of ferrous sulfate on cimetidine absorption in an in vivo isolated perfused rat jejunal model of drug absorption. The dose of cimetidine was chosen to represent a human dose of 300 mg, while the ferrous sulfate doses were chosen to represent 150- and 300-mg doses. The higher ferrous sulfate dose completely inhibited cimetidine absorption (P < 0.01), while the lower dose of ferrous sulfate caused a 63% reduction in cimetidine absorption (P < 0.05). In vitro iron in its ferrous from rapidly oxidizes to the ferric form. The ferric form of iron binds to cimetidine and may be the cause of the decreased cimetidine absorption. Care should be taken in prescribing iron supplements with cimetidine.

Animals↗

PubMed1993

The removal of metal ions from transferrin, ferritin and ceruloplasmin by the cardioprotective agent ICRF-187 [(+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] and its hydrolysis product ADR-925.

The ability of the metal ion binding rings-opened hydrolysis product of the anthracycline cardioprotective agent ICRF-187 [dexrazoxane; (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane] to remove iron from transferrin and ferritin, and copper from ceruloplasmin was examined. ADR-925 completely removed Fe3+ from transferrin at below physiological pH but was unreactive at pH 7.4. ADR-925 slowly removed copper from ceruloplasmin at physiological pH (68% removal after 4.8 days). ADR-925 was capable of removing 18% of the iron from ferritin in 7.0 days. All of the metalloproteins displayed saturation behavior in their initial rates of metal ion removal by ADR-925. ICRF-187 may be, in part, preventing doxorubicin-induced cardiotoxicity by depleting iron and copper from these storage and transport proteins or by scavenging metal ions released from these proteins, thus inhibiting hydroxyl radical production by iron-doxorubicin complexes.

Ceruloplasmin↗

PubMed1993

The one-ring open hydrolysis product intermediates of the cardioprotective agent ICRF-187 (dexrazoxane) displace iron from iron-anthracycline complexes.

The ability of the cardioprotective agent ICRF-187 (dexrazoxane), its one-ring open hydrolysis products, and its two-ring open hydrolysis product, ADR-925, to displace Fe3+ from its complex with doxorubicin, daunorubicin, epirubicin and idarubicin have been studied. At pH 7.4, ICRF-187 at a concentration of 100 microM ICRF-187 slowly but completely displaced Fe3+ from its anthracycline complexes with half-times ranging from 230 to 450 min. The one-ring open intermediate hydrolysis products were also shown to be chelating agents and were also able to displace quickly and completely Fe3+ from its anthracycline complexes with half-times ranging from 1.7 to 16.7 min. Molecular modeling of Fe3+ complexes with the one-ring open intermediates showed that these intermediates were likely acting as tetradentate ligands. Since these intermediates are such good chelating agents, they may also be pharmacologically active species in preventing oxygen-radical derived iron-based anthracycline-induced cardiotoxicity. Since these one-ring open intermediates are produced by hydrolysis from the parent ICRF-187 more quickly than is ADR-925, the formation of pharmacologically active species might be occurring more quickly than previously thought. The displacement of Fe3+ from its anthracycline complexes by the two-ring open hydrolysis product ADR-925 also took place quickly and completely with half-times ranging from 1 to 3 min.

Anthracenes↗

PubMed1993

Absence of an effect of ferrous sulfate on phenytoin absorption in the rat.

A variety of drugs which bind to iron have significant reductions in absorption when co-administered with iron compounds. The chemical structure of phenytoin indicates that there may be possible binding to iron ions. In vitro experiments were performed to determine whether any binding of iron to phenytoin occurred, and in vivo studies examined the effect of ferrous sulfate on phenytoin absorption in an isolated perfused rat jejunal model of drug absorption. The dose of phenytoin was limited by solubility and represents a human dose of 28 mg on a mg/kg basis for the rat assuming the total dose to be in 10 cm bowel in the rat. The ferrous sulfate doses were chosen to represent 28 and 300 mg doses on a similar basis to phenytoin. There was no significant effect of ferrous sulfate on phenytoin absorption or instability of phenytoin in the presence of ferrous sulfate in the rat. In vitro experiments indicated that little or no phenytoin binding to iron occurred. Results from animal model studies using low doses of phenytoin suggest it is unlikely that there will be a significant reduction in phenytoin absorption during concurrent therapy with iron salts.

Animals↗

PubMed1992

Ferrous sulfate reduces thyroxine efficacy in patients with hypothyroidism.

OBJECTIVE: To determine whether simultaneous ingestion of ferrous sulfate and thyroxine reduces the efficacy of thyroid hormone in patients with primary hypothyroidism. DESIGN: Uncontrolled clinical trial. SETTING: Outpatient research clinic of a tertiary care center. PATIENTS: Fourteen patients with established primary hypothyroidism on stable thyroxine replacement. INTERVENTION: All patients were instructed to ingest simultaneously, a 300-mg ferrous sulfate tablet and their usual thyroxine dose every day for 12 weeks. RESULTS: After 12 weeks of ferrous sulfate ingestion with thyroxine, the mean level of serum thyrotropin (thyroid stimulating hormone, TSH) rose from 1.6 +/- 0.4 to 5.4 +/- 2.8 mU/L (P < 0.01), but the free thyroxine index did not change significantly. Subjective evaluation using a clinical score showed that nine patients had an increase in symptoms and signs of hypothyroidism; the mean score for the 14 patients changed from 0 to 1.3 +/- 0.4 (P = 0.011). When iron and thyroxine were mixed together in vitro, a poorly soluble purple complex appeared that indicated the binding of iron to thyroxine. CONCLUSIONS: Simultaneous ingestion of ferrous sulfate and thyroxine causes a variable reduction in thyroxine efficacy that is clinically significant in some patients. The interaction is probably caused by the binding of iron to thyroxine.

Adult↗

PubMed1992

Norfloxacin interaction with antacids and minerals.

The urinary excretion of norfloxacin was measured in eight healthy volunteers after its co-administration with a variety of over-the-counter preparations, each containing a different metal ion. Commonly used doses of ferrous sulphate, zinc sulphate, aluminium hydroxide and magnesium hydroxide reduced the 24 h urinary excretion of norfloxacin by 50 to 90%. Bismuth subsalicylate had no significant effect. In vitro experiments demonstrated the formation of complexes between norfloxacin and iron, zinc, aluminium, and magnesium ions, respectively. Many pharmaceuticals contain the same metal ions that caused significant interactions with norfloxacin. The efficacy of norfloxacin treatment may be compromised when it is taken concurrently with preparations containing these metal ions.

Adult↗

PubMed1991

Iron supplements: a common cause of drug interactions.

Iron-drug interactions of clinical significance may occur in many patients and involve a large number of therapies. Concurrent ingestion of iron causes marked decreases in the bioavailability of a number of drugs. The affected drugs, tetracycline, tetracycline derivatives (doxycycline, methacycline and oxytetracycline), penicillamine, methyldopa, levodopa, carbidopa and ciprofloxacin have diverse chemical structures and clinical effects. The major mechanism of these drug interactions is the formation of iron-drug complexes (chelation or binding of iron by the involved drug). A large number of other important and commonly used drugs such as thyroxine, captopril and folic acid have been demonstrated to form stable complexes with iron. There is little known about the effects of concurrent therapy with iron supplements for most of the drugs.

Drug Interactions↗

PubMed1991

Clinical and chemical interactions between iron preparations and ciprofloxacin.

1. The effect of ferrous sulphate (300 mg), ferrous gluconate (600 mg), and a combination tablet of iron (10 mg), magnesium (100 mg), zinc (15 mg), calcium (162 mg), copper (2 mg), and manganese (5 mg) (Centrum Forte) co-administration on ciprofloxacin bioavailability was tested in eight healthy subjects. 2. Peak serum ciprofloxacin concentrations and area under the curve (AUC) were significantly reduced when ciprofloxacin was administered with 300 mg ferrous sulphate (3.0 vs 2.0 mg l-1, P less than 0.05 and 12.3 vs 6.7 mg l-1 h, P less than 0.01, respectively). Reductions in peak ciprofloxacin concentrations and AUC also occurred when ciprofloxacin was ingested with 600 mg ferrous gluconate (1.3 mg l-1, P less than 0.01 and 4.1 mg l-1 h, P less than 0.01, respectively) and a Centrum Forte tablet (1.4 mg l-1, P less than 0.01 and 5.4 mg l-1 h, P less than 0.01, respectively). 3. When ferrous ion was mixed with ciprofloxacin, rapid spectral changes occurred (t1/2 = 1.9 min). Additional studies were consistent with oxidation of the ferrous form of iron to its ferric form, which is followed by rapid formation of a Fe(3+)-ciprofloxacin complex. Ciprofloxacin seems to bind to ferric ion in a ratio of 3:1 by interacting with the 4-keto and 3-carboxyl groups on ciprofloxacin. 4. The formation of a ferric ion-ciprofloxacin complex is probably the cause of the reduction in ciprofloxacin bioavailability in the presence of iron.

Adult↗

PubMed1990

NADPH-cytochrome-P-450 reductase promoted hydroxyl radical production by the iron(III)-ochratoxin A complex.

The Fe3+ complex of ochratoxin A has been shown to produce hydroxyl radicals in the presence of NADPH and NADPH-cytochrome-P-450 reductase. ESR spin-trapping experiments carried out in the presence of the hydroxyl radical scavenger ethanol and the spin trap DMPO (5,5-dimethyl-1-pyrroline-1-oxide) produced ESR spectra characteristic of the hydroxyl radial-derived carbon-centered DMPO-alkoxyl radical adduct. Thus hydroxyl radicals produced by the Fe3(+)-ochratoxin A complex in the presence of an enzymatic reductase may be be partly responsible for ochratoxin A toxicity.

Electron Spin Resonance Spectroscopy↗

PubMed1990

Mechanism of ochratoxin A stimulated lipid peroxidation.

Lipid peroxidation, measured as malondialdehyde formation or by oxygen uptake, was stimulated markedly by the mycotoxin ochratoxin A (OTA) in a reconstituted system consisting of phospholipid vesicles, the flavoprotein NADPH-cytochrome P450 reductase, Fe3+, EDTA and NADPH. Deletion of EDTA lowered the extent of lipid peroxidation but did not eliminate it. Fluorometric and spectrophotometric studies demonstrated the formation of a 1:1 Fe3(+)-OTA complex. The rate of reduction of Fe3+ to Fe2+ was enhanced markedly in the presence of OTA, and there was a further increase in the rate when EDTA was also included. The data indicate that OTA stimulates lipid peroxidation by complexing Fe3+ and facilitating its reduction. Subsequent to oxygen binding, an iron-oxygen complex of undetermined nature initiates lipid peroxidation. Free hydroxyl radicals appear not to participate in lipid peroxidation stimulated by Fe3(+)-OTA.

Animals↗

PubMed1990

Inhibition and inactivation of NADH-cytochrome c reductase activity of bovine heart submitochondrial particles by the iron(III)-adriamycin complex.

The NADH-cytochrome c reductase activity of bovine heart submitochondrial particles was found to be slowly (half-time of 16 min) and progressively lost upon incubation with the Fe2(+)-adriamycin complex. In addition to this slow progressive inactivation seen on incubation, a reversible fast phase of inhibition was also seen. However, if EDTA was added to the incubation mixture within 15 s, the slow progressive loss in activity was largely preventable. Separate experiments indicated that EDTA removed about one-half of the iron from the Fe2(+)-adriamycin complex in about 40 s. These results indicated the requirement for iron for the inactivation process. Since the Vmax. for the fast phase of inhibition was decreased by the inhibitor, the inhibition pattern was similar to that seen for uncompetitive or mixed-type inhibition. The direct binding of both Fe3(+)-adriamycin and adriamycin to submitochondrial particles was also demonstrated, with the Fe3(+)-adriamycin complex binding 8 times more strongly than adriamycin. Thus binding of Fe3(+)-adriamycin to the enzyme or to the inner mitochondrial membrane with subsequent generation of oxy radicals in situ is a possible mechanism for the Fe3(+)-adriamycin-induced inactivation of respiratory enzyme activity.

Animals↗

PubMed1990

The iron(III) and copper(II) complexes of adriamycin promote the hydrolysis of the cardioprotective agent ICRF-187 ((+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane).

ICRF-187 ((+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane) has shown promise (Speyer et al., N. Engl. J. Med. 319, 745 (1988] as a cardioprotective agent against what may be an iron-based adriamycin-induced cardiotoxicity. ICRF-187, which is membrane permeable, likely exerts its action through its rings-opened hydrolysis product which has a structure similar to EDTA and which, likewise, strongly binds metal ions. Both Fe3(+)-adriamycin and Cu2(+)-adriamycin reacted directly with ICRF-187, promoting a ring-opening hydrolysis of ICRF-187 that resulted in the displacement of the metal ion from its complex with adriamycin. Thus ICRF-187 can be considered to be acting as a "suicide protective agent" in its reaction with metal ion-adriamycin complexes. That this metal ion complex-promoted hydrolysis was preceded by mixed ligand complex formation is evidenced by the fact that the first-order rate constant for loss of metal ion from the adriamycin complex exhibits saturation behaviour at high ICRF-187 concentrations. Also direct spectroscopic evidence was obtained both for a Cu2(+)-adriamycin-ICRF-187 mixed ligand complex and a Cu2+ (ICRF-187)2 complex. The Fe3(+)-adriamycin complex inactivates the cytochrome c oxidase and NADH cytochrome c reductase activity on submitochondrial particles. The protection that ICRF-187 affords against this loss of activity may be explained both on the basis of simple Fe3+ removal from Fe3(+)-adriamycin and also on formation of a less active Fe3(+)-adriamycin-ICRF-187 mixed ligand complex.

Copper↗

PubMed1990

Sinemet-ferrous sulphate interaction in patients with Parkinson's disease.

1. This study examined the effects of administering ferrous sulphate 325 mg with Sinemet (100/25 tablet) on levodopa and carbidopa bioavailability and on signs of Parkinson's disease in nine patients. 2. Ferrous sulphate ingestion with Sinemet resulted in a decrease in levodopa area under the curve (AUC) of 30% (P less than 0.01) and a greater than 75% decrease in carbidopa AUC. Despite a strong relationship between reductions in levodopa AUC and reductions in Sinemet efficacy (r = 0.83, P less than 0.01), the average reduction in Sinemet's efficacy associated with ferrous sulphate did not achieve statistical significance (P = 0.055). 3. Chemical studies indicate that iron forms chemical complexes with carbidopa in a similar manner to levodopa and is a likely mechanism for the drug interactions. 4. AUC when a Sinemet tablet is taken concurrently with a ferrous sulphate tablet appears to be clinically significant in some but not all patients. The clinical significance of repeated ingestion of ferrous sulphate with Sinemet requires further studies.

Adult↗

PubMed1990

Oxyradical production results from the Fe3(+)-doxorubicin complex undergoing self-reduction by its alpha-ketol group.

A variety of different measures have been used to compare the self-reduction of the Fe3+ complexes of doxorubicin and daunorubicin. The Fe3(+)-doxorubicin complex exhibited a much faster rate of (i) O2 consumption, (ii) self-reduction under Ar to the Fe2+ complex, (iii) aerobic reduction of ferricytochrome c, (iv) scavenging of Fe2+ by bipyridine, (v) hydroxyl radical production measured by electron paramagnetic resonance spin-trapping experiments, and (vi) inactivation of the cytochrome c oxidase activity of beef heart submitochondrial particles, than did the corresponding Fe3(+)-daunorubicin complex. In contrast to Fe3(+)-doxorubicin, the Fe3(+)-daunorubicin complex displayed only a fast phase of inhibition of the cytochrome c oxidase activity, indicating that the initial binding of these two Fe3(+)-drug complexes is very similar. All of these results indicate that Fe3(+)-doxorubicin undergoes a much faster self-reduction to the Fe2+ complex and hence a much greater rate of production of damaging oxyradicals when the Fe2+ is reoxidized by O2 or H2O2. The addition of the alpha-ketol acetol to Fe3(+)-daunorubicin resulted in greatly increased rates of (i) ferricytochrome c reduction, (ii) Fe2+ production, and (iii) hydroxyl radical production. These results support the hypothesis that the alpha-ketol functional group of doxorubicin (which is not present on daunorubicin and is the only structural difference between these two compounds) reduces the Fe3+ while undergoing oxidation itself.

Cytochrome c Group↗

PubMed1990

Ferrous sulfate reduces methyldopa absorption: methyldopa: iron complex formation as a likely mechanism.

Ferrous sulfate and sodium sulfate reduce methyldopa absorption in humans. This current study was conducted to investigate some of the potential factors by which these compounds could reduce methyldopa absorption. A rat model developed to examine drug absorption was used. Solutions of 14C methyldopa alone and with ferrous sulfate or sodium sulfate were injected in vivo into closed duodenal segments. Ferrous sulfate reduced methyldopa absorption 52.9% (p less than 0.01), while sodium sulfate had no significant effect on methyldopa absorption. In vitro iron in its ferrous form rapidly oxidizes to the ferric form in the presence of methyldopa. The ferric form of iron binds strongly to methyldopa, presumably resulting in the decreased methyldopa absorption. Methyldopa was stable in vivo and in vitro in the presence of ferrous sulfate and sodium sulfate. These studies are consistent with ferrous sulfate reducing methyldopa absorption by the formation of ferric iron: methyldopa complexes.

Animals↗

PubMed1989

The inhibition of a membrane-bound enzyme as a model for anaesthetic action and drug toxicity.

The inhibition of the membrane-bound enzyme cytochrome c oxidase by aliphatic n-alcohols and other neutral organic compounds was studied as a model for anaesthetic action and drug toxicity. The n-alcohols (C1 to C14) displayed a variation in inhibition constant of over 500,000-fold. The inhibition constants correlated well with the number of carbon atoms in the n-alcohols and also their n-octanol/water partition coefficients. General anaesthetic potency is known to be similarly well correlated with octanol/water partition coefficients. The free-energy change for transferring a methylene group of the n-alcohol to the more hydrophobic environment bound to the enzyme is similar to that for transferring a methylene group from water to pure alcohol. These results are consistent with the n-alcohols inhibiting by binding to an octanol-like environment on the enzyme or the protein/phospholipid interface. Neither negatively charged carboxylates nor positively charged amine analogues were observed to cause any inhibition, indicating that this postulated binding site may be uncharged. Inhibition of cytochrome c oxidase by n-alcohols was also demonstrated in both bovine heart and rat liver sonicated submitochondrial fragments.

Alcohols↗